OR23-3 Hunger Hormone Asprosin Activates Orexigenic Neurons via SK Currents

Neurons that co-express the orexigenic agouti-related protein (AgRP) and neuropeptide Y (NPY) are indispensable for normal feeding behavior. Firing activities of AgRP/NPY neurons dynamically fluctuate with energy status and coordinate appropriate feeding behavior to meet nutritional demands. We previously demonstrated that asprosin, a recently discovered fasting-induced glucogenic and orexigenic hormone, crosses the blood-brain barrier and directly activates the orexigenic AgRP/NPY neurons via a cyclic cAMP-dependent pathway. However, intrinsic mechanisms on how asprosin regulates AgRP/NPY neural activities during the fed-to-fasted transition are not fully understood. In the satiated mice with low circulating levels of asprosin, we found that AgRP/NPY neurons expressed high levels of the small conductance calcium-activated potassium channel 3 (SK3) and were inhibited by SK3-mediated potassium currents. Conversely, in 24 hour-fasting mice with high levels of asprosin, AgRP/NPY neurons expressed low levels of SK3 and were activated via inhibition of SK3-mediated potassium currents. Notably, the stimulatory effects of asprosin on AgRP/NPY neurons were blunted in mice with SK3 selectively deleted in the AgRP/NPY neurons, further supporting a mediating role of SK3. Moreover, we also identified protein tyrosine phosphatase receptor δ (Ptprd), a membrane-bound phosphatase receptor, as the orexigenic asprosin-receptor. Deletion of Ptprd in AgRP/NPY neurons abolished asprosin's stimulatory effect on SK3-mediated currents and protected mice from diet-induced obesity. Lastly, increased circulating levels of asprosin promoted hyperphagia, body weight gain, and glucose intolerance. On the other hand, anti-asprosin antibody treatment decreased food intake and body weight by inhibiting AgRP/NPY and other orexigenic hypothalamic neurons via SK currents stimulation. In summary, our data support a model that asprosin acts on Ptprd expressed by AgRP/NPY neurons to inhibit SK3 current, further activating AgRP/NPY neurons to increase food intake and body weight. Our findings also provided preclinical evidence that asprosin-neutralizing antibodies could be used to treat obesity. Presentation: Monday, June 13, 2022 11:45 a.m. - 12:00 p.m.